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Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M. Thomsen, Yvonne Wang, Andra Mihali, Caroline Sferrazza, Ilana Zucker-Scharff, Anna-Claire Siena, Martha G. Welch, José Lizardi-Ortiz, David Sulzer, Holly Moore, Inna Gaisler-Salomon, Stephen Rayport
doi: https://doi.org/10.1101/154864
Susana Mingote
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
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Nao Chuhma
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
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Abigail Kalmbach
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
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Gretchen M. Thomsen
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
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Yvonne Wang
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
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Andra Mihali
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
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Caroline Sferrazza
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
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Ilana Zucker-Scharff
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
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Anna-Claire Siena
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
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Martha G. Welch
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
3Department of Pediatrics, Columbia University
4Department of Developmental Neuroscience, NYS Psychiatric Institute
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José Lizardi-Ortiz
5Department of Neurology, Columbia University
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David Sulzer
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
5Department of Neurology, Columbia University
6Department of Pharmacology, Columbia University
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Holly Moore
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
7Department of Integrative Neuroscience, NYS Psychiatric Institute
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Inna Gaisler-Salomon
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
8Department of Psychology, University of Haifa, Haifa 3498838, Israel
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Stephen Rayport
1Department of Psychiatry, Columbia University, New York, NY 10032, USA
2Department of Molecular Therapeutics, NYS Psychiatric Institute, New York, NY 10032, USA
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  • For correspondence: stephen.rayport@columbia.edu
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ABSTRACT

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene GLS1). In mice with a DAT-driven conditional heterozygous (cHET) reduction of GLS1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling focusing the cotransmission. DAT GLS1 cHET mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 23, 2017.
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Dopamine neuron dependent behaviors mediated by glutamate cotransmission
Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M. Thomsen, Yvonne Wang, Andra Mihali, Caroline Sferrazza, Ilana Zucker-Scharff, Anna-Claire Siena, Martha G. Welch, José Lizardi-Ortiz, David Sulzer, Holly Moore, Inna Gaisler-Salomon, Stephen Rayport
bioRxiv 154864; doi: https://doi.org/10.1101/154864
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Dopamine neuron dependent behaviors mediated by glutamate cotransmission
Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M. Thomsen, Yvonne Wang, Andra Mihali, Caroline Sferrazza, Ilana Zucker-Scharff, Anna-Claire Siena, Martha G. Welch, José Lizardi-Ortiz, David Sulzer, Holly Moore, Inna Gaisler-Salomon, Stephen Rayport
bioRxiv 154864; doi: https://doi.org/10.1101/154864

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